Familial Hemophagocytic Lymphohistiocytosis Type 5 (FHL-5) Is Caused by Mutations in Munc18-2 and Impaired Binding to Syntaxin 11
Familial Hemophagocytic Lymphohistiocytosis Type 5 (FHL-5) Is Caused by Mutations in Munc18-2 and Impaired Binding to Syntaxin 11
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DOI：
10.1016/j.ajhg.2009.09.005
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发表时间：
2009-10-09
影响因子：
9.8
通讯作者：
Hennies, Hans Christian
中科院分区：
文献类型：
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作者：
zur Stadt, Udo;Rohr, Jan;Hennies, Hans Christian
细胞毒性颗粒通过免疫突触的快速细胞内运输和分泌需要几种蛋白质的平衡相互作用。这一高度调节的过程的紊乱是家族性噬血细胞性淋巴组织细胞增生症（FHL）的基础，FHL是一种遗传异质性常染色体隐性遗传疾病，其特征是严重的炎症表型。在这里，我们已经分配FHL-5染色体19 p上的1 Mb区域，通过使用高分辨率SNP基因分型在8个无关的FHL患者的血缘家庭。随后，我们在来自土耳其、沙特阿拉伯和中欧的12名患者中发现了9种不同的STXBP 2突变，无论是截短还是错义。STXBP 2编码突触融合蛋白结合蛋白2（Munc 18 -2），参与调节囊泡转运至质膜。我们已经确定了syntaxin 11，一种在FHL-4中突变的SNARE蛋白，作为STXBP 2的相互作用伴侣。在我们的FHL-5患者中发现的错义突变消除了这种相互作用，这导致两种蛋白质的稳定性降低，如患者淋巴细胞所示。通过CD 107脱粒测定，自然杀伤和细胞毒性T细胞的活性显著降低或不存在。因此，我们的研究结果确定了STXBP 2在溶解颗粒胞吐中的关键作用。
Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 in lytic granule exocytosis.